FDA label 169a0bc3-c3b5-dae6-080c-9d0cd4f63d21

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with TECHNIVIE. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions ( 5.1 )] . WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation : Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( 5.1 ) Hepatic Decompensation and Hepatic Failure in Patient with Cirrhosis : Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported mostly in patients with cirrhosis. Monitor for clinical signs and symptoms of hepatic decompensation, and discontinue treatment in patients who develop evidence of hepatic decompensation. ( 5.2 ) ALT Elevations : Discontinue ethinyl estradiol-containing medications prior to starting TECHNIVIE (alternative contraceptive methods are recommended). Perform hepatic laboratory testing on all patients during the first 4 weeks of treatment. For ALT elevations on TECHNIVIE, monitor closely and follow recommendations in full prescribing information. ( 5.3 ) Risks Associated With Ribavirin Combination Treatment : The warnings and precautions for ribavirin also apply to this combination regimen. ( 5.4 ) Drug Interactions : The concomitant use of TECHNIVIE and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of TECHNIVIE. ( 5.5 ) 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with TECHNIVIE. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with TECHNIVIE and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. 5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported in clinical trials and postmarketing in patients treated with ombitasvir, paritaprevir, ritonavir with and without ribavirin. Most patients with these severe outcomes had evidence of cirrhosis prior to initiating therapy. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation. TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Contraindications ( 4 ), Adverse Reactions ( 6.2 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . For patients with compensated cirrhosis: Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage). Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated. Discontinue TECHNIVIE in patients who develop evidence of hepatic decompensation. 5.3 Increased Risk of ALT Elevations During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of subjects [see Adverse Reactions ( 6.1 )] . ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing. These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with TECHNIVIE [see Contraindications ( 4 )] . Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended during TECHNIVIE therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with TECHNIVIE. Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens. Due to the limited number of subjects taking these other estrogens in clinical studies, caution is warranted for co-administration with TECHNIVIE [see Adverse Reactions ( 6.1 )] . Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely: Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Consider discontinuing TECHNIVIE if ALT levels remain persistently greater than 10 times the ULN. Discontinue TECHNIVIE if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR. 5.4 Risks Associated With Ribavirin Combination Treatment The warnings and precautions for ribavirin, in particular the pregnancy avoidance warning and use in patients with cardiac disease, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration ( 2.1 )] . 5.5 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions The concomitant use of TECHNIVIE and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of TECHNIVIE and possible development of resistance Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of TECHNIVIE. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions ( 7 )] . Consider the potential for drug interactions prior to and during TECHNIVIE therapy; review concomitant medications during TECHNIVIE therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] . 5.6 Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients The ritonavir component of TECHNIVIE is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with TECHNIVIE should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with TECHNIVIE. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with TECHNIVIE and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported in clinical trials and postmarketing in patients treated with ombitasvir, paritaprevir, ritonavir with and without ribavirin. Most patients with these severe outcomes had evidence of cirrhosis prior to initiating therapy. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation. TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Contraindications ( 4 ), Adverse Reactions ( 6.2 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . For patients with compensated cirrhosis: Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage). Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated. Discontinue TECHNIVIE in patients who develop evidence of hepatic decompensation.

5.4 Risks Associated With Ribavirin Combination Treatment The warnings and precautions for ribavirin, in particular the pregnancy avoidance warning and use in patients with cardiac disease, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration ( 2.1 )] .

6 ADVERSE REACTIONS TECHNIVIE should be administered with ribavirin (RBV). Refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions. The following adverse reaction is described below and elsewhere in the labeling: Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis [see Warnings and Precautions ( 5.2 )] Increased Risk of ALT Elevations [see Warnings and Precautions ( 5.3 )] The most commonly reported adverse reactions (incidence greater than 10% of subjects, all grades) observed with treatment with ombitasvir, paritaprevir and ritonavir with ribavirin for 12 weeks in patients without cirrhosis were asthenia, fatigue, nausea and insomnia. ( 6.1 ) The most common adverse events (incidence greater than 10% of subjects, all grades) observed with treatment with TECHNIVIE and ribavirin for 12 weeks in patients in compensated cirrhosis were fatigue, asthenia, headache, musculoskeletal pain, pruritus, insomnia/sleep disorder, skin reactions, mood disorders, nausea, dizziness and dyspnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reaction in Subjects without Cirrhosis The safety assessment of TECHNIVIE is based on data from two clinical studies in subjects with HCV genotype 4 infection. PEARL-I was a study including 135 subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks. Adverse reactions that occurred in subjects without cirrhosis treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 2 . The majority of adverse reactions in non-cirrhotic subjects were mild in severity, none were serious and none led to discontinuation of treatment. Table 2. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection without Cirrhosis Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks PEARL-I Without Cirrhosis Adverse Reaction Ombitasvir, paritaprevir, ritonavir + RBV N = 91 % Ombitasvir, paritaprevir, ritonavir N = 44 % Asthenia 29 25 Fatigue 15 7 Nausea 14 9 Insomnia 13 5 Pruritus 1 7 5 Skin reactions 2,3 7 5 1 Grouped term ‘pruritus’ includes the preferred terms pruritus and pruritus generalized. 2 Grouped term ‘skin reactions’ includes the preferred terms rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer and urticaria. 3 The majority of events were graded as mild in severity. Adverse Events in Subjects with Compensated Cirrhosis AGATE-I was a study including 120 subjects with compensated cirrhosis who received TECHNIVIE once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in Table 3 . Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of TECHNIVIE. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin. Table 3. Selected Adverse Events (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection with Compensated Cirrhosis Treated with TECHNIVIE and Ribavirin through 12 Weeks AGATE-I Compensated Cirrhosis Adverse Events TECHNIVIE + RBV N=120 (%) Fatigue 25 Asthenia 25 Headache 23 Musculoskeletal Pain/Changes 1 17 Pruritus 16 Insomnia/Sleep Disorder 2 14 Skin Reactions 3 13 Dyspnea 4 11 Mood Disorders 5 11 Nausea 11 Dizziness 11 Cardiac Events 6 9 Abdominal Pain 7 9 Cough 7 Clinical Liver or Bilirubin Related Events 8 7 Edema 9 6 Altered Mental Status 10 6 Decreased Appetite 6 Vomiting 6 1 Grouped term ‘musculoskeletal pain/changes’ includes the preferred terms arthralgia, arthritis, back pain, muscle injury, muscle spasms, muscular weakness, musculoskeletal chest pain, myalgia, neck pain, and pain in extremity. 2 Grouped term ‘insomnia/sleep disorder’ includes preferred terms insomnia and sleep disorder. 3 Grouped term ‘skin reactions’ includes preferred terms dermatitis bullous, dermatitis psoriasiform, dry skin, eczema asteatotic, erythema, rash, skin exfoliation, skin lesion and skin toxicity. 4 Grouped term ‘dyspnea’ includes preferred terms dyspnea and dyspnea exertional. 5 Grouped term ‘mood disorders’ includes preferred terms affective disorder, agitation, anxiety, depressed mood, depression, irritability, mania and suicide attempt. 6 Grouped term ‘cardiac events’ includes preferred terms acute coronary syndrome, angina pectoris, atrial fibrillation, chest pain, hypertension, hypotension and palpitations. 7 Grouped term ‘abdominal pain’ includes preferred terms abdominal discomfort, abdominal pain, abdominal pain lower and abdominal pain upper. 8 Grouped term ‘clinical liver or bilirubin related events’ includes preferred terms ascites, hepatic encephalopathy, jaundice, ocular icterus, esophageal varices hemorrhage and portal vein thrombosis. 9 Grouped term ‘edema’ includes preferred terms edema and edema peripheral. 10 Grouped term ‘altered mental status’ includes preferred terms disturbance in attention, memory impairment, psychomotor retardation and somnolence. Laboratory Abnormalities Serum ALT Elevations None of the 135 subjects without cirrhosis and two (2%) of the 120 subjects with compensated cirrhosis treated with TECHNIVIE experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) and ≥2 times baseline after starting treatment [see Warnings and Precautions ( 5.3 )] . Serum Bilirubin Elevations in Patients without Cirrhosis Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects without cirrhosis, receiving TECHNIVIE, all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations. Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations. Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis. One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites. Anemia/Decreased Hemoglobin in Patients without Cirrhosis The mean change from baseline in hemoglobin levels in subjects without cirrhosis treated with TECHNIVIE in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with TECHNIVIE alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. One subject treated with TECHNIVIE with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. No subject treated with TECHNIVIE alone had hemoglobin levels less than 8 g/dL. Four percent (4/91) of subjects without cirrhosis treated with TECHNIVIE with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels. No subject received erythropoietin. Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment. One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population. Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of TECHNIVIE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Anaphylactic reactions and other hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions ( 5.3 )] . Skin and Subcutaneous Tissue Disorders : Erythema multiforme (EM).

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reaction in Subjects without Cirrhosis The safety assessment of TECHNIVIE is based on data from two clinical studies in subjects with HCV genotype 4 infection. PEARL-I was a study including 135 subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks. Adverse reactions that occurred in subjects without cirrhosis treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 2 . The majority of adverse reactions in non-cirrhotic subjects were mild in severity, none were serious and none led to discontinuation of treatment. Table 2. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection without Cirrhosis Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks PEARL-I Without Cirrhosis Adverse Reaction Ombitasvir, paritaprevir, ritonavir + RBV N = 91 % Ombitasvir, paritaprevir, ritonavir N = 44 % Asthenia 29 25 Fatigue 15 7 Nausea 14 9 Insomnia 13 5 Pruritus 1 7 5 Skin reactions 2,3 7 5 1 Grouped term ‘pruritus’ includes the preferred terms pruritus and pruritus generalized. 2 Grouped term ‘skin reactions’ includes the preferred terms rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer and urticaria. 3 The majority of events were graded as mild in severity. Adverse Events in Subjects with Compensated Cirrhosis AGATE-I was a study including 120 subjects with compensated cirrhosis who received TECHNIVIE once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in Table 3 . Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of TECHNIVIE. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin. Table 3. Selected Adverse Events (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection with Compensated Cirrhosis Treated with TECHNIVIE and Ribavirin through 12 Weeks AGATE-I Compensated Cirrhosis Adverse Events TECHNIVIE + RBV N=120 (%) Fatigue 25 Asthenia 25 Headache 23 Musculoskeletal Pain/Changes 1 17 Pruritus 16 Insomnia/Sleep Disorder 2 14 Skin Reactions 3 13 Dyspnea 4 11 Mood Disorders 5 11 Nausea 11 Dizziness 11 Cardiac Events 6 9 Abdominal Pain 7 9 Cough 7 Clinical Liver or Bilirubin Related Events 8 7 Edema 9 6 Altered Mental Status 10 6 Decreased Appetite 6 Vomiting 6 1 Grouped term ‘musculoskeletal pain/changes’ includes the preferred terms arthralgia, arthritis, back pain, muscle injury, muscle spasms, muscular weakness, musculoskeletal chest pain, myalgia, neck pain, and pain in extremity. 2 Grouped term ‘insomnia/sleep disorder’ includes preferred terms insomnia and sleep disorder. 3 Grouped term ‘skin reactions’ includes preferred terms dermatitis bullous, dermatitis psoriasiform, dry skin, eczema asteatotic, erythema, rash, skin exfoliation, skin lesion and skin toxicity. 4 Grouped term ‘dyspnea’ includes preferred terms dyspnea and dyspnea exertional. 5 Grouped term ‘mood disorders’ includes preferred terms affective disorder, agitation, anxiety, depressed mood, depression, irritability, mania and suicide attempt. 6 Grouped term ‘cardiac events’ includes preferred terms acute coronary syndrome, angina pectoris, atrial fibrillation, chest pain, hypertension, hypotension and palpitations. 7 Grouped term ‘abdominal pain’ includes preferred terms abdominal discomfort, abdominal pain, abdominal pain lower and abdominal pain upper. 8 Grouped term ‘clinical liver or bilirubin related events’ includes preferred terms ascites, hepatic encephalopathy, jaundice, ocular icterus, esophageal varices hemorrhage and portal vein thrombosis. 9 Grouped term ‘edema’ includes preferred terms edema and edema peripheral. 10 Grouped term ‘altered mental status’ includes preferred terms disturbance in attention, memory impairment, psychomotor retardation and somnolence. Laboratory Abnormalities Serum ALT Elevations None of the 135 subjects without cirrhosis and two (2%) of the 120 subjects with compensated cirrhosis treated with TECHNIVIE experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) and ≥2 times baseline after starting treatment [see Warnings and Precautions ( 5.3 )] . Serum Bilirubin Elevations in Patients without Cirrhosis Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects without cirrhosis, receiving TECHNIVIE, all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations. Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations. Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis. One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites. Anemia/Decreased Hemoglobin in Patients without Cirrhosis The mean change from baseline in hemoglobin levels in subjects without cirrhosis treated with TECHNIVIE in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with TECHNIVIE alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. One subject treated with TECHNIVIE with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. No subject treated with TECHNIVIE alone had hemoglobin levels less than 8 g/dL. Four percent (4/91) of subjects without cirrhosis treated with TECHNIVIE with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels. No subject received erythropoietin. Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment. One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population. Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension).

6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of TECHNIVIE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Anaphylactic reactions and other hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions ( 5.3 )] . Skin and Subcutaneous Tissue Disorders : Erythema multiforme (EM).

<table ID="table_2" border="1" width="100%"> <caption>Table 2. Selected Adverse Reactions (All Grades) with &#x2265;5% Frequency Reported in Subjects with HCV Genotype 4 Infection without Cirrhosis Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks</caption> <colgroup> <col width="33*"/> <col width="33*"/> <col width="33*"/> </colgroup> <tbody> <tr> <td styleCode="Toprule Botrule Lrule Rrule"> </td> <td styleCode="Toprule Botrule Lrule Rrule" colspan="2" align="center"> <content styleCode="bold">PEARL-I Without Cirrhosis</content> </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center"> <content styleCode="bold">Adverse Reaction</content> </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center"> <content styleCode="bold">Ombitasvir, paritaprevir, ritonavir + RBV N = 91 %</content> </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center" valign="top"> <content styleCode="bold">Ombitasvir, paritaprevir, ritonavir N = 44 %</content> </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Asthenia</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">29</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">25</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Fatigue</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">15</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">7</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Nausea</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">14</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">9</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Insomnia</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">13</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">5</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Pruritus¹ </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">7</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">5</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Skin reactions^2,3 </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">7</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">5</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" colspan="3"> ¹Grouped term &#x2018;pruritus&#x2019; includes the preferred terms pruritus and pruritus generalized. ²Grouped term &#x2018;skin reactions&#x2019; includes the preferred terms rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer and urticaria. ³The majority of events were graded as mild in severity.</td> </tr> </tbody> </table>